SBIR TOPIC 255

前列腺癌是美国男性癌症死亡的第二大原因。制定控制前列腺癌的战略对公共卫生至关重要。前列腺特异性抗原（PSA）是一种可能的免疫治疗靶点，研究表明树突状细胞在引发有效的免疫应答中起着重要作用。在此应用中，为了表达PSA，将使用Medigen的新TC83载体，该载体与体内淋巴组织和树突状细胞相关（Pushko, 2005）。进一步，我们提出了合理设计和优化PSA，以提高其免疫原性/治疗特性。TC83载体将被配置成在体内表达以下抗原：(1)可溶性PSA (sPSA)；(2)低聚PSA (oligoPSA)；3)膜结合PSA （tmPSA）。将生成表达sPSA、寡聚opsa或tmPSA基因的载体病毒样颗粒（vvlp），并将其用于实验性PSA tg小鼠体内表达基因，从而引发对合成PSA的免疫反应。假设使用TC-83载体和合理设计PSA将通过包括靶向树突和交叉呈递在内的其他途径将体内免疫原性提高10,000倍。将评估合成疫苗的免疫原性、安全性和可行性。

Prostate cancer is the second leading cause of mortality from cancer among men in the US. The development of strategies for control of prostate cancer is essential for public health. Prostate-specific antigen (PSA) is a likely target for immunotherapy, and research has indicated the important role of dendritic cells in eliciting effective immune response. In this application, for expression of PSA, Medigen's new TC83 vector will be used that is associated with targeting lymphoid tissue and dendritic cells in vivo (Pushko, 2005). Further, we propose the rational design and optimization of PSA in order to enhance its immunogenic/therapeutic characteristics. The TC83 vector will be configured to express in vivo the following antigens: (1) soluble PSA (sPSA); (2) oligomeric PSA (oligoPSA); and (3) membrane-bound PSA (tmPSA). Vector virus-like particles (vVLPs) for expression of sPSA, oligoPSA, or tmPSA gene will be generated and administered to experimental PSA tg mice to express genes in vivo, thus eliciting immune responses to synthetic PSA. The hypothesis is that the use of TC-83 vector and the rational design of PSA will increase immunogenicity in vivo up to 10,000 times through additional pathways including targeting of dendritic and cross-presentation. Immunogenicity, safety, and feasibility of synthetic vaccines will be evaluated.